A number of anti-angiogenic therapies that target the vascular endothelial growth factor (VEGF) ligand/receptor family are currently in development and clinical trials. VEGF stimulates division and proliferation of the endothelial cells, induces onset of neovascualrization, and provides oxygen and nutrition to the tissue cells.
A highly effective method for VEGF ligand blockade in the treatment of cancer is the use of soluble VEGF receptors such as VEGFR-1 (FLT-1) or VEGFR-2 (KDR). In the construction of these molecules, extracellular IgG-like domains of the VEGF receptors that are responsible for binding the VEGF ligand have been fused to the human IgG1 heavy chain fragment with a signal sequence at the N-terminus for secretion.
The membrane-bound tyrosine kinase receptor, known as FLT, was shown to be a VEGF receptor (DeVries, C. et al., 1992, Science, 255, pp. 989-991), which specifically binds VEGF and induces mitogenesis. Another form of the VEGF receptor, designated KDR, is also known to bind VEGF and induce mitogenesis. (Terman, B. I. et al., 1991 Oncogene 6, pp. 1677-1683; Terman, B. I. et al., 1992 Biochem. Biophys. Res. Comm. 187, pp. 1579-1586).
Persistent angiogenesis can cause neovascularization, which may result in or exacerbate eye disorders such as age-related macular degeneration, diabetic retinopathy, diseases including tumor vascularization in various cancers, psoriasis and rheumatoid arthritis.
Retinal vessels and chordial vessels are the essential components of the retina. Abnormal changes in the vessel wall structure and function of the blood vessels caused by trauma or disease can lead to hypopsia and visual loss.
Many studies have shown that once photoreceptor cells of the retina degenerate (ischemic atrophy) because of lack of nutrition, the concentration of VEGF in the retina starts to increase to promote neovascularization. This process is called angiogenesis. In the eyes, the newly generated blood vessels have different morphology from normal blood vessels in that the vessel lumen is irregular and the tissue wall is often leaky. This kind of abnormal growth of highly permeable or leaky blood vessels often results in scarring of the retina, and loss of vision.
There remains a need for clinical development of a safe and efficacious inhibitor of VEGF activity that has a favorable stability and pharmacokinetic profiles and is useful in treatment of disease associated with neovascularization, in particular, angiogenesis-related eye disease. The present invention addresses this need.